A multifunctional DECM/PLMA hydrogel incorporated with engineered PRP-derived exosomes enabling PHD2 silencing for skin wound repair

Scaffold-mediated delivery of a miRNA-29b mimic mitigates excessive extracellular matrix deposition and matrix contraction in wound healing applications

Disruption of the wound healing cascade can result in pathological outcomes, including fibrosis due to myofibroblast-mediated contraction and collagen deposition. Despite the clinical significance, effective treatments for fibrosis remain limited as current therapies often show inconsistent efficacy, adverse effects, and patient discomfort. Combinatorial therapeutic strategies integrating biomaterial scaffolds with gene delivery have shown promise in regenerative healing. MicroRNAs (miRNAs) are key regulators of fibrotic signalling in cells, including fibroblasts and myofibroblasts. Specifically, miRNA-29b is notable for downregulating pro-fibrotic genes, including collagen type I, reducing ECM accumulation, and limiting fibroblast/myofibroblast overactivation. In this context, the present work develops a collagen-GAG (CG) scaffold platform for delivery of miRNA-29b complexed GET nanoparticles to inhibit fibrosis. Initially, bioinformatic analysis of miRNA-29b validated its involvement in ECM-associated pathways and processes, followed by successful nanoparticle internationalisation in primary dermal fibroblasts. The anti-fibrotic efficacy of the optimised miRNA-29b nanoparticles was subsequently demonstrated by significant reductions in collagen deposition and α-SMA expression, both key indicators of myofibroblast differentiation and fibrosis. The optimised miRNA-29b formulation was then incorporated into 3D porous collagen-GAG (CG) scaffolds, which modulated fibrotic gene expression while preserving scaffold structure conducive to fibroblast/myofibroblast infiltration and proliferation. Finally, functional outcomes of seeded TGF-β-stimulated fibroblasts, including reduced matrix contraction, α-SMA expression, and ECM deposition, were comparable to those observed in non-fibrotic conditions, thereby confirming the therapeutic potential of scaffold-mediated miRNA- 29b delivery. Together, these findings demonstrate that scaffold-mediated miRNA-29b delivery represents a promising anti-fibrotic strategy for wound healing by mitigating myofibroblast activation, limiting matrix contraction, and preventing pathological ECM accumulation. Highlights miRNA-29b delivery mitigates fibrosis via collagen and α-SMA attenuation Scaffold-mediated miRNA-29b delivery inhibits fibrosis-related matrix contraction Scaffold-mediated miRNA-29b delivery mitigates excessive extracellular matrix deposition Graphical Abstract

Single-cell transcriptomics-guided dynamic hydrogel delivery of artemisia argyi-derived EVs relieves ER stress and promotes diabetic wound regeneration.

Diabetic wounds are characterized by persistent inflammation, impaired angiogenesis, and delayed tissue regeneration, yet effective strategies to regulate the pathological immune microenvironment remain limited. Here, integrated single-cell transcriptomics and multi-omics analyses revealed significant enrichment of endoplasmic reticulum stress (ERS)-related signaling in pro-inflammatory macrophages within diabetic wounds, suggesting a potential mechanism driving chronic inflammation. To target this process, we developed an injectable dynamic hydrogel (GPOK-2@EVs) incorporating Artemisia argyi-derived extracellular vesicles (EVs) for localized immunomodulatory therapy. The hydrogel was formed through dual dynamic crosslinking between phenylboronic acid-modified gelatin and oxidized konjac glucomannan, providing self-healing capability, injectability, tissue adhesion, and pH/ROS-responsive degradation for sustained EV release. In vitro experiments demonstrated that GPOK-2@EVs exhibited excellent biocompatibility and effectively reprogrammed macrophages toward an anti-inflammatory phenotype, accompanied by reduced inflammatory cytokine secretion, alleviated ERS activation, decreased ROS accumulation, and improved mitochondrial integrity. GPOK-2@EVs significantly enhanced endothelial angiogenic activities, including cytoskeletal remodeling, tube formation, and migration. In a diabetic mouse wound model, GPOK-2@EVs accelerated wound closure, promoted granulation tissue formation and collagen deposition, enhanced vascularization, and suppressed inflammatory and ERS responses. These findings demonstrate that EV-loaded dynamic hydrogels can modulate the inflammatory microenvironment and promote diabetic wound regeneration, providing a promising biomaterial strategy for chronic wound therapy.

A Hierarchical Hydrogel Modulates Immune-Mechanical Microenvironments to Spatiotemporally Reprogram Fibroblasts for Scarless Diabetic Wound Healing.

In vivo studies in diabetic Sprague-Dawley rats model demonstrated that CC-pMnO2-Vet@PNAA established a coordinated immune-mechanical microenvironment, achieving rapid and scar-free wound healing.

A Tissue-Homologous Keratin-PBA Hydrogel Integrating Rationally Designed Nanomicelles Enables Microenvironment-Adaptive Repair of Chronic Diabetic Wounds.

Chronic diabetic wounds require continuous modulation of the hyperglycemia-induced pathological microenvironment. Although glucose-responsive biomaterials show promise for diabetic wound treatment, intelligent wound management with tissue specificity and multifactorial repair capacity remains urgently needed. Here, we develop a tissue-homologous, glucose-responsive hydrogel based on epidermis-derived keratin functionalized with phenylboronic acid (Keratin-PBA), which is crosslinked with oxidized sodium alginate (OSA) to form a double-network hydrogel (cOK) and integrated with bioactive nanomicelles for adaptive wound microenvironment regulation. Co-assembled nanomicelles (OA-PG NMs), composed of oleanolic acid (OA) and propyl gallate (PG), exhibit glucose-triggered release and complementary bioactivities targeting oxidative stress, inflammation, macrophage polarization, angiogenesis, fibroblast behavior, antibacterial activity, and MMP regulation. Notably, OA promotes angiogenesis via the TGR5-Akt-eNOS-NO signaling pathway. The resulting cOK@NM hydrogel enables spatiotemporally controlled nanomicelle release and significantly accelerates diabetic wound healing in vivo, as evidenced by rapid wound closure, enhanced M2 macrophage polarization, robust neovascularization, improved collagen remodeling, reduced AGEs, broad-spectrum antibacterial effects against E. coli and S. aureus, and increased granulation tissue formation. This work presents a tissue-homologous, intelligently adaptive platform integrating intrinsic regenerative bioactivity with glucose-responsive therapeutic adaptability.

Study on the physicochemical properties of MSCs exosome-loaded viscous hydrogels and their mechanism of regulating angiogenesis

Naringin-based hydrogel decorated 3D printed scaffold modulates immunity and angiogenesis for diabetic bone regeneration

Hyperglycemia and inflammation within the diabetic microenvironment impair the healing of bone defects in diabetic patients. A key limitation of current therapeutic approaches is their lack of efficacy in restoring immune homeostasis. Herein, a novel 3D-printed PHSN composite scaffold is designed to regulate the immune microenvironment. PHSN is fabricated by integrating poly (lactic-co-glycolic acid) (PLGA) with hydroxyapatite (HA) via 3D printing technology, yielding a structure that combines osteogenic potential with mechanical strength. Loaded with naringin and SupGels, PHSN promotes macrophage repolarization toward the M2 phenotype via the JAK/STAT signaling pathway, thereby upregulating anti-inflammatory mediators and tissue-regeneration factors, stimulating angiogenesis and osteogenesis. In diabetic models, PHSN inhibits M1 macrophage polarization, drives reprogramming toward the M2 phenotype, and upregulates the expression of CD31, ALP, and OCN at bone defect sites, indicating enhanced angiogenesis and osteogenesis. Collectively, this study establishes a strategy of synergistically modulating immunity, vascularization, and bone formation, offering a promising and translatable solution for diabetic bone regeneration.